The Cardiovascular Health Study-Cognition Study (CHS-CS), "Predictors of Alzheimer's disease (AD) in mild cognitive impairment (MCI)" (AG 20098) has carefully followed 532 non-demented participants over the past 3 years. These were 83% of the 924 eligible participants from the original CHS Pittsburgh cognition study initially established in 1992- 94. The participants have been followed with annual neuropsychological evaluations, information from informants and detailed clinical information. By 2006, 32% of the normals (approximately 6% per year) and 63% of the MCIs (approximately 16% per year) will be demented; and 359 are alive in 2006, with a mean age of 86. This study has shown that most MCI convert to dementia, that many normals convert to dementia very rapidly, that the MRI findings are crucial for understanding risk, including vascular disease in the brain, global brain atrophy and focal brain abnormalities. The proposed 4-year renewal includes 3 years of follow up and repeat MRIs for the surviving cohort in order to evaluate the characteristics of individuals who survive free of dementia to determine the relationship of risk factors and MRI changes over an approximate 18-20 year follow up for the 924 participants, to analyze the relationship of lifestyles, genetic and MRI attributes to the risk of dementia, MCI and remaining normal. Most of the resources in this proposed follow up are dedicated to the detailed evaluation of the MRIs, to careful evaluation of the remaining survivors and for detailed final analysis. This is the only large population-based study for the foreseeable future with long term follow up, repeat MRIs and careful neuropsychological evaluation. From the data gathered in the first 3 years of this project, we have developed a central hypothesis to guide our research questions. Specifically, that the pathological state of AD exists years prior to the development of the clinical signs/symptoms of the dementia syndrome. We view MCI as the transitional state between normal cognition and frank dementia, and that in the absence of other comorbid conditions, MCI is AD. In this context, our study of the variables that indicate the presence of neuropathological change (e.g., structural and perfusion MRI, plasma beta-amyloid) and the factors that modify the risk to express the clinical syndrome takes on an added importance. The goals of this study are to examine the natural history of AD, from a normal cognitive state to dementia onset, with especial emphasis on the transitional phase (Mild Cognitive Impairment (MCI)). This analysis will be conducted in a context of a large cohort using detailed medical information, and it constitutes an integrative approach to truly understand the development of AD and MCI in the general population. [unreadable] [unreadable] [unreadable] [unreadable]